Invariant natural killer T (iNKT) cells have important tumor immunosurveillance properties, and their activation with pharmacological agents is associated with tumour clearance in animal models. The archetypal iNKT cell agonist, α-galactoseceramide (α-GalCer, shown below) is a glycolipid that is currently being used in a limited number of clinical trials for the treatment of lung, myeloma, and head and neck tumors. Treatment with α-GalCer often results in side-effects, such as activation induced anergy of iNKT cells (i.e. long-term unresponsiveness to repeated α-GalCer treatment) and dendritic cell (DC) lysis by iNKT cells following presentation of α-GalCer. Loss of circulating levels of iNKT cells could represent a therapeutically significant limitation with iNKT-cell-based therapies if multi-dosing regimens are required.
α-Galactosylceramide

A group of nonglycosidic ceramides that substantially mimic the binding properties of α-GalCer with the human CD1d molecule, but differs significantly in the interaction with T-cell receptors (TCR) compared to α-GalCer is described in U.S. Patent Application Publication No. 2009/0239813 and Silk et al., J. of Immunol. 180:6452-6456 (2008), each incorporated herein by reference. These compounds, such as threitolceramide (TC) and glycerolceramide, are able to sensitize murine and human iNKT cells and, like α-GalCer, maintain potent anti-tumor responses in animal models. Some of these nonglycosidic ceramides display poor water solubility, however, which can limit their use clinically. A need exists for the effective delivery of nonglycosidic ceramides for clinical applications.